The central hypothesis of this proposal is that, in addition to binding to retinoid receptors, some of the retinoids also activate xenobiotic receptors. This "dual action" may be responsible for conflicting results in previous studies examining the putative therapeutic effects of retinoids. Activation of xenobiotic receptors can lead to cancer promotion by inhibiting apoptosis, inducing proliferation and increasing the expression of phase I enzymes that bioactivate carcinogen. Thus, the therapeutic and "counter-therapeutic" (cancer promoting) effects of retinoids or other nuclear receptor ligands can be differentiated based on the type of nuclear receptors that is activated and the ligand's relative effect on regulating phase I bioactivation or phase II detoxification processes. Our work during the current funding period of this project demonstrated that retinoid x receptor (RXR)-mediated pathways control both phase I bioactivation and phase II detoxification. We also showed that some retinoids, which were expected to have chemopreventive or chemotherapeutic activities, could also activate xenobiotic receptors and induce phase I enzyme expression, and thus potentially can promote xenobiotic toxicity. Most importantly, those retinoids activate human steroid and xenobiotic receptor (SXR) and therefore their effects are clinically important. Retinoids are widely used as daily food supplements and therapeutic regiments for medical conditions. The long-term consequences of CYP450 enzyme induction are of great concern. Thus, it is essential to elucidate the mechanism(s) responsible for their deleterious effects. Our proposed studies aim at distinguishing the therapeutic vs. cancer promoting effects of carotenoids/retinoids and distinguishing inducers that differentially regulate phase I and II reactions. The proposed studies will screen commonly used carotenoids/retinoids for their effects on xenobiotic receptor activation, CYP450 induction, tumor promotion, drug-drug interaction as well as anti-apoptosis and pro-apoptosis. The mechanisms mediating the positive and negative effects of retinoids will be analyzed. The proposed study will also examine the role of nuclear receptors in regulating phase II reactions. Bifunctional (ligands that induces both phase I and ID and monofunctional (ligands that mainly induce phase II) inducers will be identified. The identification of specific regulatory pathways will greatly enhance our ability to develop selective therapeutic targets. A particularly exciting possibility is that, by identifying elements of the regulatory pathways that may be coordinated, we would be in an advantageous position formulate innovative, efficient treatment strategies. The information derived from the proposed study is thus crucial for the successful clinical application of existing retinoids as well as for the future development of new and increasingly more effective intervention methods.